Targeting the mTOR Pathway

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Introduction

The mammalian target of rapamycin, or mTOR, is a long, fancy name for a protein that belongs to the PIKK (phosphoinositol kinase-related kinase) enzyme family. mTOR is involved in cell growth regulation in response to nutrients (such as amino acids), growth factors, hormones (such as insulin), and other stimulants or mitogens. The mTOR enzyme also contributes to many other critical cellular functions, including protein production, protein degradation, and angiogenesis. mTOR is present in all cells, but often has molecular changes when expressed in tumor cells. These changes are thought to make tumor cells more vulnerable to mTOR inhibition than normal cells would be, which in turn makes this an attractive potential anti-tumor therapy.

Current mTOR inhibitors work by first binding to a molecule called FKBP12. This combo then forms a three-part complex with mTOR, thereby rendering the mTOR inactive. Thus they inhibit indirectly, but with specificity.

Current mTOR Inhibitors

CCI 779 was first studied in the clinic in 1999, and is available in both intravenous and oral formulations. Phase Ib/II studies have shown limited activity in renal cell and prostate cancers, but some more promising clinical response in breast cancer. Current phase II studies are looking at patients with renal cell cancer who have poor prognosis, and breast cancer patients, either with or without hormone therapy.

AP23573 is a very potent intravenous mTOR inhibitor. It is relatively safe and has mild to moderate adverse effects, with mucositis as the dose-limiting toxicity. This drug has a lot of desirable features. First, it has predictable pharmacokinetics, meaning that it has a consistent half-life in a patient's blood (48 hrs if given weekly, 61 hrs if given daily). Also, it is not a pro-drug that then has to be metabolized by the body into the active compound. This is an important aspect when using this drug in combination with other therapies. Finally, the level of mTOR inhibition corresponds nicely with the levels of AP23573 in the patient's blood. A phase II study in patients with advanced sarcoma showed remarkable clinical benefit in all 4 sarcoma subgroups (bone, leiomyosarcoma, liposarcoma, and other soft tissue sarcomas). Improvements were seen in tumor-related symptoms such as pain, cough, shortness of breath, as well as on objective measures such as PET scan. Trials investigating the predictive utility of PET imaging in patients treated with AP23573 are underway.

Sep 19, 2014 - The investigational drug alpelisib (previously known as BYL719) appears to inhibit activation of the pathway that leads to resistance to cetuximab, an anti-epidermal growth factor receptor agent used in the treatment of head and neck cancer. These findings were presented at the American Association for Cancer Research's special conference "Targeting the PI3K-mTOR Network in Cancer," held from Sept. 14 to 17 in Philadelphia.